tbuckley/cabot-search huggingface dataset:
AMPK and the Endocrine Control of Metabolism
Authors: Logan K Townsend, Gregory R Steinberg
Journal: Endocrine Reviews (2023)

Complex multicellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors such as fasting, cold, and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, glucagon-like peptide-1, catecholamines, ghrelin, and fibroblast growth factor 21; adipokines such as leptin and adiponectin; cell stress-induced cytokines like tumor necrosis factor alpha and growth differentiating factor 15, and lastly exerkines such as interleukin-6 and irisin. Over the last 2 decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (adenosine monophosphate-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100 distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol, and protein metabolism. In this review, we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.
Macrophages in the synovial lining niche initiate neutrophil recruitment and articular inflammation
Authors: Kristina Zec, Barbora Schonfeldova, Zhichao Ai, Erinke Van Grinsven, Gabriela Pirgova, Hayley L. Eames, Dorothée L. Berthold, Moustafa Attar, Ewoud B. Compeer, Tal I. Arnon, Irina A. Udalova
Journal: The Journal of Experimental Medicine (2023)

The first immune-activating changes within joint resident cells that lead to pathogenic leukocyte recruitment during articular inflammation remain largely unknown. In this study, we employ state-of-the-art confocal microscopy and image analysis in a systemic, whole-organ, and quantitative way to present evidence that synovial inflammation begins with the activation of lining macrophages. We show that lining, but not sublining macrophages phagocytose immune complexes containing the model antigen. Using the antigen-induced arthritis (AIA) model, we demonstrate that on recognition of antigen–antibody complexes, lining macrophages undergo significant activation, which is dependent on interferon regulatory factor 5 (IRF5), and produce chemokines, most notably CXCL1. Consequently, at the onset of inflammation, neutrophils are preferentially recruited in the vicinity of antigen-laden macrophages in the synovial lining niche. As inflammation progresses, neutrophils disperse across the whole synovium and form swarms in synovial sublining during resolution. Our study alters the paradigm of lining macrophages as immunosuppressive cells to important instigators of synovial inflammation.
Molecular and clinicopathologic characterization of pediatric histiocytoses
Authors: Zofia Hélias‐Rodzewicz, Jean Donadieu, Nathalie Terrones, Mohamed‐Aziz Barkaoui, Anne Lambilliotte, Despina Moshous, Caroline Thomas, Saba Azarnoush, Marlène Pasquet, Ludovic Mansuy, Nathalie Aladjidi, Eric Jeziorski, Perrine Marec‐Berard, Marion Gilibert‐Yvert, Alexandra Spiegel, Paul Saultier, Isabelle Pellier, Anne Pagnier, Sophie Pertuisel, Maryline Poiree, Damien Bodet, Frédéric Millot, Florentina Isfan, Jean‐Louis Stephan, Amaury Leruste, Charlotte Rigaud, Bruno Filhon, Liana Carausu, Yves Reguerre, Isabelle Kieffer, Bénédicte Brichard, Rim Ben Jannet, Mariama Bakari, Ahmed Idbaih, Christine Bodemer, Fleur Cohen‐Aubart, Julien Haroche, Abdellatif Tazi, Sabah Boudjemaa, Sylvie Fraitag, Jean‐François Emile, Sébastien Heritier
Journal: American Journal of Hematology (2023)

Abstract The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non‐Langerhans cell histiocytosis (‐LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAF V600E . Most BRAF WT samples were analyzed by next‐generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim‐Chester disease, 21 Rosai‐Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAF V600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non‐ BRAF V600E ‐mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 ( n = 44), BRAF exon 12 deletions ( n = 26), and duplications ( n = 8), other BRAF V600 codon mutation ( n = 4), and non‐MAP‐kinase pathway genes ( n = 5). Wild‐type sequences were identified in 17.1% of samples. BRAF V600E was the only variant significantly correlated with critical presentations: organ‐risk involvement and neurodegeneration. MAP‐kinase pathway mutations were identified in seven RDD (mostly MAP2K1 ) and three JXG samples, but most samples were wild‐type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAF G469R mutation. Rarely, we identified mutations unrelated to MAP‐kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.
Innate immune pathway modulator screen identifies STING pathway activation as a strategy to inhibit multiple families of arbo and respiratory viruses
Authors: Gustavo Garcia, Joseph Ignatius Irudayam, Arjit Vijey Jeyachandran, Swati Dubey, Christina Chang, Sebastian Castillo Cario, Nate Price, Sathya Arumugam, Angelica L. Marquez, Aayushi Shah, Amir Fanaei, Nikhil Chakravarty, Shantanu Joshi, Sanjeev Sinha, Samuel W. French, Mark S. Parcells, Arunachalam Ramaiah, Vaithilingaraja Arumugaswami
Journal: Cell Reports Medicine (2023)

RNA viruses continue to remain a threat for potential pandemics due to their rapid evolution. Potentiating host antiviral pathways to prevent or limit viral infections is a promising strategy. Thus, by testing a library of innate immune agonists targeting pathogen recognition receptors, we observe that Toll-like receptor 3 (TLR3), stimulator of interferon genes (STING), TLR8, and Dectin-1 ligands inhibit arboviruses, Chikungunya virus (CHIKV), West Nile virus, and Zika virus to varying degrees. STING agonists (cAIMP, diABZI, and 2',3'-cGAMP) and Dectin-1 agonist scleroglucan demonstrate the most potent, broad-spectrum antiviral function. Furthermore, STING agonists inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enterovirus-D68 (EV-D68) infection in cardiomyocytes. Transcriptome analysis reveals that cAIMP treatment rescue cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provides protection against CHIKV in a chronic CHIKV-arthritis mouse model. Our study describes innate immune signaling circuits crucial for RNA virus replication and identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses.
Applications of single-cell RNA sequencing in drug discovery and development
Authors: Bram Van de Sande, Joon Sang Lee, Euphemia Mutasa-Gottgens, Bart Naughton, Wendi Bacon, Jonathan Manning, Yong Wang, Jack Pollard, Melissa Mendez, Jon Hill, Namit Kumar, Xiaohong Cao, Xiao Chen, Mugdha Khaladkar, Ji Wen, Andrew Leach, Edgardo Ferran
Journal: Nature Reviews Drug Discovery (2023)

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery and development. New opportunities are emerging in target identification owing to improved disease understanding through cell subtyping, and highly multiplexed functional genomics screens incorporating scRNA-seq are enhancing target credentialling and prioritization. ScRNA-seq is also aiding the selection of relevant preclinical disease models and providing new insights into drug mechanisms of action. In clinical development, scRNA-seq can inform decision-making via improved biomarker identification for patient stratification and more precise monitoring of drug response and disease progression. Here, we illustrate how scRNA-seq methods are being applied in key steps in drug discovery and development, and discuss ongoing challenges for their implementation in the pharmaceutical industry. There have been significant recent advances in the development of single-cell technologies, providing remarkable opportunities for drug discovery and development. Here, Ferran and colleagues discuss how single-cell technologies, primarily single-cell RNA sequencing methods, are being applied in the drug discovery pipeline, from target identification to clinical decision-making. Ongoing challenges and potential future directions are discussed.
Correction: Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology
Authors: Wenhui Qiao, Yixing Chen, Jun Zhong, Benjamin J. Madden, Cristine M. Charlesworth, Yuka A. Martens, Chia-Chen Liu, Joshua Knight, Tadafumi C. Ikezu, Aishe Kurti, Yiyang Zhu, Axel Meneses, Cassandra L. Rosenberg, Lindsey A. Kuchenbecker, Lucy K. Vanmaele, Fuyao Li, Kai Chen, Francis Shue, Maxwell V. Dacquel, John Fryer, Akhilesh Pandey, Na Zhao, Guojun Bu
Journal: Molecular Neurodegeneration (2023)
Re: Ana Cavillon, Damien Pouessel, Nadine Houédé, et al. Assessing Long-term Treatment Benefits Using Complementary Statistical Approaches: An In Silico Analysis of the Phase III Keynote-045 and Checkmate-214 Immune Checkpoint Inhibitor Trials. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2023.02.011
Authors: Binghao Zhao, Ruidong Zhang, Jiaming Wu
Journal: European Urology (2023)
PD-1 Inhibitors Prolong Survival in Leptomeningeal Disease
Journal: Cancer Discovery (2023)

According to interim results of a phase I trial, patients with melanoma and leptomeningeal disease who received intrathecal and intravenous nivolumab, a PD-1 inhibitor, experienced a median overall survival of 4.9 months compared with a historical average of about 6 weeks with radiation and chemotherapy. No dose-limiting toxicities were reported.
An In Vitro and Ex Vivo Analysis of the Potential of GelMA Hydrogels as a Therapeutic Platform for Preclinical Spinal Cord Injury
Authors: Ciara M. Walsh, Jacek K. Wychowaniec, Louise Costello, Dermot F. Brougham, Dearbhaile Dooley
Journal: Advanced Healthcare Materials (2023)

Abstract Spinal cord injury (SCI) is a devastating condition with no curative therapy currently available. Immunomodulation can be applied as a therapeutic strategy to drive alternative immune cell activation and promote a proregenerative injury microenvironment. Locally injected hydrogels carrying immunotherapeutic cargo directly to injured tissue offer an encouraging treatment approach from an immunopharmacological perspective. Gelatin methacrylate (GelMA) hydrogels are promising in this regard, however, detailed analysis on the immunogenicity of GelMA in the specific context of the SCI microenvironment is lacking. Here, the immunogenicity of GelMA hydrogels formulated with a translationally relevant photoinitiator is analyzed in vitro and ex vivo. 3% ( w/v ) GelMA, synthesized from gelatin type‐A, is first identified as the optimal hydrogel formulation based on mechanical properties and cytocompatibility. Additionally, 3% GelMA‐A does not alter the expression profile of key polarization markers in BV2 microglia or RAW264.7 macrophages after 48 h. Finally, it is shown for the first time that 3% GelMA‐A can support the ex vivo culture of primary murine organotypic spinal cord slices for 14 days with no direct effect on glial fibrillary acidic protein (GFAP + ) astrocyte or ionized calcium‐binding adaptor molecule 1 (Iba‐1 + ) microglia reactivity. This provides evidence that GelMA hydrogels can act as an immunotherapeutic hydrogel‐based platform for preclinical SCI.
Internet-based and mobile-based cognitive behavioral therapy for chronic diseases: a systematic review and meta-analysis
Authors: Tiffany Junchen Tao, Teck Kuan Lim, Ernest Tsun Fung Yeung, Huinan Liu, Phoenix Bibha Shris, Lawrence Ka Yin Ma, Tatia Mei Chun Lee, Wai Kai Hou
Journal: npj Digital Medicine (2023)

Positive adjustment to chronic diseases reduces psychiatric comorbidity and enhances quality of life. Very little is known about the benefit of internet-based and mobile-based Cognitive Behavioral Therapy (IM-CBT) on physical outcomes and its reciprocal interactions with psychiatric outcomes, the active therapeutic elements, and effect moderators among people with major chronic medical conditions. In this systematic review and meta-analysis (PROSPERO: CRD42022265738), CINAHL of Systematic Reviews, MEDLINE, PsycINFO, PubMed, Web of Science are systematically searched up to 1 June 2022, for randomized controlled trials (RCTs) comparing IM-CBT against non-CBT control condition(s) among people with chronic disease(s). Primary outcomes include improvements in psychiatric symptoms (depressive, anxiety, PTSD symptoms, general psychological distress) from baseline to post-intervention and follow-ups. Secondary outcomes include improvements in physical distress (physical symptoms, functional impairment, self-rated ill health, objective physiological dysfunction). Among 44 RCTs (5077 patients with seven different chronic diseases), IM-CBT improves depressive symptoms, anxiety symptoms, and general psychological distress at post-intervention and across follow-ups, and improves physical distress and functional impairment at post-intervention. Preliminary evidence suggests that behavioral modification and problem-solving could be necessary components to reduce psychiatric symptoms in IM-CBT, whereas cognitive restructuring, psychoeducation, and mindfulness elements relate to reduced physical distress. IM-CBT shows stronger benefits in chronic pain, cancer, arthritis, and cardiovascular disease, relative to other conditions. Changes in psychiatric symptoms and physical distress prospectively predict each other over time. IM-CBT is an effective intervention for comprehensive symptom management among people with chronic diseases.
Epidemiology, clinical features and outcome of adults with meningococcal meningitis: a 15-year prospective nationwide cohort study
Authors: Thijs M. van Soest, Nora Chekrouni, Nina M. van Sorge, Merijn W. Bijlsma, Matthijs C. Brouwer, Diederik van de Beek
Journal: The Lancet Regional Health - Europe (2023)

We describe the epidemiology, clinical features and outcome of adult meningococcal meningitis in the Netherlands over a 15-year period.We studied adults (age ≥ 16 years) who were listed by the Netherlands Reference Laboratory for Bacterial Meningitis and/or included in the prospective nationwide cohort study (MeninGene) between January 2006 and July 2021. Incidences were calculated per epidemiological year (July-June).We identified 442 episodes of adult meningococcal meningitis. The median patient age was 32 years (IQR 18-55) and 226 episodes (51%) occurred in female patients. The annual incidence per 100,000 adults fluctuated, from 0.33 in 2006-2007 to 0.05 in 2020-2021, with a temporal increase up to 0.30 from 2016 to 2018, driven by an outbreak of serogroup W (MenW). Of 442 episodes, 274 episodes (62%) in 273 patients were included in the clinical cohort study. The overall case fatality rate was 4% (10 of 274) and 16% (43 of 274) had an unfavourable outcome (Glasgow Outcome Scale score 1-4). Compared to other serogroups, MenW was associated with higher rates of unfavourable outcome (6 of 16 [38%] vs. 37 of 251 [15%], P = 0.03) and death (4 of 16 [25%] vs. 6 of 251 [2%], P = 0.001).The overall incidence of adult meningococcal meningitis in the Netherlands is low and outcome is generally favourable. An increase of MenW meningitis occurred from 2016 to 2018, which was associated with more unfavourable outcome and death.Netherlands Organisation for Health Research and Development, European Research Council, National Institute of Public Health and Environmental protection.
Biomimetic Periodontal Ligament Transplantation Activated by Gold Nanoparticles Protects Alveolar Bone
Authors: Chen Zong, Wannes Van Holm, Annelies Bronckaers, Zuodong Zhao, Stevan Čokić, Merve Kübra Aktan, Ana Belén Castro, Bart Van Meerbeek, Annabel Braem, Guy Willems, Maria Cadenas de Llano‐Pérula
Journal: Advanced Healthcare Materials (2023)

Abstract Stem cell therapy might be a promising method to stimulate alveolar bone regeneration, which is currently a major clinical challenge. However, its therapeutic features largely depend on pretreatment and transplantation preparation. Herein, a novel biomimetic periodontal ligament transplantation composed of human periodontal ligament stem cells (hPDLSCs) pretreated with gold nanocomplexes (AuNCs) and embedded in a type‐I collagen hydrogel scaffold is developed to protect alveolar bone from resorption. AuNCs are readily absorbed by primary hPDLSCs, with limited cytotoxicity, and promote osteogenic differentiation of hPDLSCs effectively in vitro. In addition, the AuNCs‐induced hPDLSCs are encapsulated with type‐I collagen hydrogel scaffold to mimic their native physiological niche, and then are transplanted into a rat model of alveolar bone resorption. Both micro‐computed tomography (micro‐CT) and immunohistochemical assays demonstrate that alveolar bone loss is significantly prevented. Furthermore, the underlying therapeutic mechanism is elucidated, in which transplantation‐activated osteogenesis is associated with autophagy, which enables bone remodeling and regeneration. This study provides critical insight into the role of PDLSCs in bone homeostasis and proposes an innovative AuNCs‐based strategy for stem cell therapy in bone regeneration.
Intratumoral microbial heterogeneity affected tumor immune microenvironment and determined clinical outcome of HBV-related HCC
Authors: Shengnan Li, Han Xia, Zeyu Wang, Xiehua Zhang, Tianqiang Song, Jia Li, Liang Xu, Ningning Zhang, Shu Fan, Qian Li, Qiaoling Zhang, Yingnan Ye, Jiayu Lv, Xiaofen Yue, Hongcheng Lv, Jinpu Yu, Wei Lu
Journal: Hepatology (2023)

Background and Aims: The intratumoral microbiome has been reported to regulate the development and progression of cancers. We aimed to characterize intratumoral microbial heterogeneity (IMH) and establish microbiome-based molecular subtyping of HBV-related HCC to elucidate the correlation between IMH and HCC tumorigenesis. Approach and Results: A case-control study was designed to investigate microbial landscape and characteristic microbial signatures of HBV-related HCC tissues adopting metagenomics next-generation sequencing. Microbiome-based molecular subtyping of HCC tissues was established by nonmetric multidimensional scaling. The tumor immune microenvironment of 2 molecular subtypes was characterized by EPIC and CIBERSORT based on RNA-seq and verified by immunohistochemistry. The gene set variation analysis was adopted to explore the crosstalk between the immune and metabolism microenvironment. A prognosis-related gene risk signature between 2 subtypes was constructed by the weighted gene coexpression network analysis and the Cox regression analysis and then verified by the Kaplan-Meier survival curve. IMH demonstrated in HBV-related HCC tissues was comparably lower than that in chronic hepatitis tissues. Two microbiome-based HCC molecular subtypes, defined as bacteria- and virus-dominant subtypes, were established and significantly correlated with discrepant clinical-pathologic features. Higher infiltration of M2 macrophage was detected in the bacteria-dominant subtype with to the virus-dominant subtype, accompanied by multiple upregulated metabolism pathways. Furthermore, a 3-gene risk signature containing CSAG4 , PIP4P2 , and TOMM5 was filtered out, which could predict the clinical prognosis of HCC patients accurately using the Cancer Genome Atlas data. Conclusions: Microbiome-based molecular subtyping demonstrated IMH of HBV-related HCC was correlated with a disparity in clinical-pathologic features and tumor microenvironment (TME), which might be proposed as a biomarker for prognosis prediction of HCC.
Viral epidemic preparedness: a perspective from five clinical microbiology laboratories in Europe
Authors: Miguel Julián Martínez, Matthew Cotten, My V.T. Phan, Karsten Becker, Mateu Espasa, Truls M. Leegaard, Gorm Lisby, Uffe Vest Schneider, Climent Casals-Pascual
Journal: Clinical Microbiology and Infection (2023)

Pandemic preparedness is critical to respond effectively to existing and emerging/new viral pathogens. Important lessons have been learned during the last pandemic at various levels. This revision discusses some of the major challenges and potential ways to address them in the likely event of future pandemics.
The impact of the American Academy of Dermatology/International League of Dermatological Societies COVID-19 Registry during the pandemic: 2500 cases across 72 countries
Authors: Alexis G. Strahan, Janet E. Lubov, Sonya Prasad, Lindy P. Fox, Devon E. McMahon, Rhea Singh, Misha Rosenbach, Seemal R. Desai, Henry W. Lim, Bruce H. Thiers, George J. Hruza, Lars E. French, Esther E. Freeman
Journal: Journal of the American Academy of Dermatology (2023)
Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a likely antigenic target in membranous nephropathy and nonsteroidal anti-inflammatory drug use
Authors: Sanjeev Sethi, Marta Casal Moura, Benjamin Madden, Hanna Debiec, Samih H. Nasr, Christopher P. Larsen, LouAnn Gross, Vivian Negron, Raman Deep Singh, Karl A. Nath, Aaron J. Storey, Ulrich Specks, Fernando C. Fervenza, Pierre Ronco, Tiffany N. Caza
Journal: Kidney International (2023)

Drugs are an important secondary cause of membranous nephropathy (MN) with the most common drugs associated with MN being nonsteroidal anti-inflammatory drugs (NSAIDs). Since the target antigen in NSAID-associated MN is not known, we performed laser microdissection of glomeruli followed by mass spectrometry (MS/MS) in 250 cases of PLA2R-negative MN to identify novel antigenic targets. This was followed by immunohistochemistry to localize the target antigen along the glomerular basement membrane and western blot analyses of eluates of frozen biopsy tissue to detect binding of IgG to the novel antigenic target. MS/MS studies revealed high total spectral counts of a novel protein Proprotein Convertase Subtilisin/Kexin Type 6 (PCSK 6) in five of the 250 cases in the discovery cohort. A validation cohort using protein G immunoprecipitation, MS/MS, and immunofluorescence detected PCSK6 in eight additional cases. All cases were negative for known antigens. Ten of 13 cases had a history of heavy NSAID use with no history available in one case. The mean serum creatinine and proteinuria at kidney biopsy were 0.93 ± 0.47 mg/dL and 6.5 ± 3.3 gms/day, respectively. Immunohistochemistry/immunofluorescence showed granular staining for PCSK6 along the glomerular basement membrane, and confocal microscopy showed co-localization of IgG and PCSK6. IgG subclass analysis in three cases revealed codominance of IgG1 and IgG4. Western blot analysis using eluates from frozen tissue showed IgG binding to PCSK6 in PCSK6-associated but not in PLA2R-positive MN. Thus, PCSK6 may be a likely novel antigenic target in MN in patients with prolonged NSAID use.